| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048816 |
| E.1.2 | Term | Lennox-Gastaut syndrome |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of GWP42003-P as adjunctive treatment in reducing the number of drop seizures when compared with placebo, in patients with LGS.
Drop seizure is defined as an attack or spell (atonic, tonic, or tonic-clonic) involving the entire body, trunk or head that led or could have led to a fall, injury, slumping in a chair or hitting the patient’s head on a surface. |
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| E.2.2 | Secondary objectives of the trial |
To assess the following in LGS patients taking GWP42003-P as adjunctive treatment, when compared with placebo:
Key:
• Number of patients drop seizure-free.
• Responder rate, in terms of reduction in drop seizures.
• Reduction in the number of non-drop seizures.
• Frequency of subtypes of seizures.
• Safety and tolerability of GWP42003-P through monitoring of:
− AEs, Suicidal ideation, Abuse liability, Cannabis withdrawal effects, Clinical laboratory tests, Vital signs.
− Menstruation cycles (in females).
Other:
• Number of episodes of status epilepticus.
• Need for hospitalization due to epilepsy.
• Change in duration of subtypes of seizures.
• Sleep disruption and daytime sleepiness.
• Quality of life, Adaptive behavior, Cognitive function, Growth and development.
• To determine the PKs of CBD and its major metabolites following single and multiple doses of GWP42003-P.
• To determine effects of GWP42003-P on plasma concentrations of concomitant AEDs, where available. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patient and/or parent(s)/legal representative must be willing and able to give informed assent/consent for participation in the study.
• Patient and their caregiver must be willing and able (in the investigator’s opinion) to comply with all study requirements.
• Patient must be male or female aged between two and 55 years (inclusive).
• Patient must have a clinical diagnosis of LGS. This includes written documentation of having met electroencephalogram (EEG) diagnostic criteria during the patient’s history and evidence of more than one type of generalized seizure, including drop seizures (atonic, tonic or tonic-clonic), for at least six months. Care should be taken not to include benign myoclonic epilepsy of infancy, atypical benign partial epilepsy (pseudo-Lennox syndrome), or continuous spike-waves of slow sleep.
• Patients who have a history of slow (<3.0 Hz) spike-and-wave pattern in an EEG prior to the enrollment into the baseline period.
• Patients must have at least two drop seizures each week during the first 28 days of the baseline period.
• Patients should be refractory; that is having documented failures on more than one AED.
• Patient must be taking one or more AEDs at a dose which has been stable for at least four weeks prior to screening.
• All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation [VNS]) must have been stable for four weeks prior to screening and patient is willing to maintain a stable regimen throughout the study. The ketogenic diet and VNS treatments are not counted as an AED.
• Patient and/or parent(s)/legal representative is willing to allow his or her primary care practitioner and consultant to be notified of participation in the study.
• Patient has completed their Interactive Voice Response System (IVRS) telephone diary on at least 25 days of the baseline period. |
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| E.4 | Principal exclusion criteria |
• Etiology of patient's seizures is a progressive neurologic disease. Patients with tuberous sclerosis will not be excluded from study participation, unless there is a progressive tumor.
• Patient has had an anoxic episode requiring resuscitation within six months of screening.
• Patient has clinically significant unstable medical conditions other than epilepsy.
• Patient has had clinically relevant symptoms or a clinically significant illness in the four weeks prior to screening or randomization, other than epilepsy.
• Patient has clinically significant abnormal laboratory values, in the investigator’s opinion, at screening or randomization.
• Patient has clinically relevant abnormalities in the ECG measured at screening or randomization.
• Patient has any concurrent cardiovascular conditions, which will, in the investigators opinion, interfere with the ability to assess their ECGs.
• Patient has a history or presence of alcohol or substance abuse within the last two years prior to the study or daily consumption of five or more alcohol-containing beverages.
• Patient is currently using or has in the past used recreational or medicinal cannabis, or synthetic cannabinoid based medications (including Sativex®) within the three months prior to study entry.
• Patient is unwilling to abstain from using recreational or medicinal cannabis, or synthetic cannabinoid based medications (including Sativex) during the study.
• Patient has a history of symptoms (e.g., dizziness, light-headedness, blurred vision, palpitations, weakness, syncope) related to a drop in blood pressure due to postural changes.
• Patient has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP, such as sesame oil.
• Female patient is of child bearing potential or male patient’s partner is of child bearing potential; unless willing to ensure that they or their partner use a highly effective method of contraception for the duration of the study and for three months thereafter. Highly effective methods of contraception are defined as those, alone or in combination, that result in low failure rate (i.e., less than 1% per year) when used consistently and correctly. Such methods include hormonal contraceptives, intrauterine devices/ hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence.
• Female patient is pregnant (positive pregnancy test), lactating or planning pregnancy during the course of the study and for three months thereafter.
• Patient has been part of a clinical trial involving another IMP in the previous six months.
• Any other significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, may influence the result of the study, or affect the patient’s ability to participate in the study.
• Patient has significantly impaired hepatic function at screening (Visit 1) or randomization (Visit 2), defined as any of the following:
− Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal (ULN).
− ALT or AST >3 × ULN and (total bilirubin [TBL] >2 × ULN or international normalized ratio [INR] >1.5).
− ALT or AST >3 × ULN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
This criterion can only be confirmed once the laboratory results are available; patients randomized into the study who are later found to meet this criterion must be withdrawn from the study.
• Following a physical examination, the patient has any abnormalities that, in the opinion of the investigator, would prevent the patient from safe participation in the study.
• Any history of suicidal behavior or any suicidal ideation of type four or five on the C-SSRS in the last month or at screening.
• Patient is unwilling to abstain from donation of blood during the study.
• There are plans for the patient to travel outside their country of residence during the study.
• Patient has previously been randomized into this study.
• Patient is taking more than four concurrent AEDs.
• Patient has taken corticotropins in the six months prior to screening.
• Patient is currently taking long-term systemic steroids (excluding inhaled medication for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception will be made for prophylactic medication, for example, for idiopathic nephrotic syndrome or asthma.
• Patient is taking felbamate, and they have been taking it for less than one year prior to screening. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the mean percentage change from baseline in number of drop seizures (average per 28 days) during the treatment period (Day 1 to the end of the evaluable period) in patients taking GWP42003-P compared with placebo. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The baseline period is Screening (V1)- Randomisation (V2). Mean percentage change from baseline in number of drop seizures (average per 28 days) during the treatment period (Day 1 to the end of the evaluable period) in patients taking GWP42003-P compared with placebo. |
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| E.5.2 | Secondary end point(s) |
The following endpoints will be compared between treatment groups over the 14-week, double-blind treatment period, unless specified otherwise:
• Percentage change from baseline in number of drop seizures (average per 28 days) during the Weeks 1–4, 5–8 and 9–12 of the maintenance period.
• Number of patients considered treatment responders, defined as those with a ≥25%, ≥50%, ≥75%, or 100% reduction in drop seizures from baseline (overall and four-weekly).
• Number of patients experiencing a >25% worsening, −25 to +25% no change, 25–50% improvement, 50–75% improvement or >75% improvement in drop seizures from baseline.
• Percentage change from baseline in number of non-drop seizures (average per 28 days).
• Percentage change from baseline in the frequencies of subtypes of seizures (average per 28 days).
• Changes from baseline in duration of seizure subtypes as assessed by the Subject/Caregiver Global Impression of Change in Seizure Duration (S/CGICSD).
• Changes from baseline in number of episodes of status epilepticus.
• Changes from baseline in number of inpatient hospitalizations due to epilepsy.
• Changes from baseline in quality of life as assessed by the Quality of Life in Childhood Epilepsy (QOLCE), for patients aged between two and 18 years of age, or Quality of Life in Epilepsy, version 2, (QOLIE-31-P) for patients aged 19 years and older.
• Changes from baseline in the Subject/Caregiver Global Impression of Change (S/CGIC) score.
• Change from baseline in adaptive behavior as measured with the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) score.
• Change from baseline in cognitive function as measured with the Cognitive Assessment Battery.
• Changes from baseline in Sleep Disruption 0–10 Numerical Rating Scale (0–10 NRS) score.
• Changes from baseline in Epworth Daytime Sleepiness Scale (EDSS) score.
• Change from baseline in growth and development for patients less than 18 years of age by measurement of height, weight, , insulin-like growth factor-1 (IGF-1) levels and Tanner Staging (for patients aged 10–17 years [inclusive], or earlier if clinically indicated by onset of menarche or other signs of precocious puberty).
PK:
The plasma concentration/time curve of CBD and its major metabolites will be described following single and multiple doses of GWP42003-P, with the aim being to define:
− Peak plasma concentration (Cmax)
− Time to peak plasma concentration (tmax)
− Area under the plasma concentration-time curve from time zero to infinity (AUC(0–∞)) or to the last measurable concentration (AUC(0–tz))
− Terminal half-life (t½)
• Plasma concentrations of concomitant AEDs before and after treatment with GWP42003-P, where available.
The safety profile of GWP42003-P compared with placebo will also be assessed by measuring:
• AEs.
• Clinical laboratory parameters.
• Columbia-Suicide Severity Rating Scale (C-SSRS) score.
• Vital signs.
• Physical examination parameters.
• 12-lead electrocardiogram (ECG).
• Cannabis Withdrawal Scale (CWS) or Pediatric Cannabinoid Withdrawal Scale (PCWS) score, as appropriate.
• Abuse liability.
• Effects on menstruation cycles (in females). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The baseline period is Screening (V1) - Randomisation (V2). Mean percentage change from baseline will be measured over the 14-week, double-blind treatment period, unless specified otherwise, in patients taking GWP42003-P compared with placebo. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Netherlands |
| Poland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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